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This study investigated how IL\u201021\u2010induced STAT3 and IL\u20102\u2010induced STAT5 activation in pTfh cells affects vaccine responses in aging people with HIV (PWH) and those without HIV (PWoH). Ninety participants, including young (Y, \u2264\u200940\u2009years) and old (O, \u2265\u200965\u2009years) PWoH (YPWoH,\n                    <jats:italic>n<\/jats:italic>\n                    \u2009=\u200923; OPWoH,\n                    <jats:italic>n<\/jats:italic>\n                    \u2009=\u200925) and virally suppressed PWH (YPWH,\n                    <jats:italic>n<\/jats:italic>\n                    \u2009=\u200919; OPWH,\n                    <jats:italic>n<\/jats:italic>\n                    \u2009=\u200923), received the seasonal quadrivalent influenza vaccine. Samples were collected at pre\u2010vaccination (day 0) and at days 14 and 28 post\u2010vaccination. Participants were classified as vaccine responders (VR) or non\u2010responders (VNR) based on serum antibody titers against vaccine antigens using the hemagglutination inhibition assay. Phosphoflow cytometry was performed on pre\u2010vaccination PBMCs stimulated with IL\u201021 or IL\u20102, and high\u2010dimensional analysis was performed using OMIQ software. Peripheral Tfh cells of young individuals showed greater IL\u201021\u2010induced STAT3, reduced IL\u20102\u2010induced STAT5 activity, and a reduced frequency of IL\u20102R+ pTfh cells compared to older individuals. IL\u201021\u2010induced STAT3 in na\u00efve CD4+ T cells in young participants correlated with the frequency of pTfh cells. Among VNR, IL\u20102\u2010induced STAT5 in pTfh cells inversely correlated with day 28 vaccine titers. Our findings emphasize the essential role of IL\u201021 and IL\u20102\u2010induced STAT signaling in orchestrating the immune response to vaccination. As individuals age, IL\u20102\u2010induced STAT5 signaling in pTfh increases, potentially hindering Tfh cell differentiation and function, which may result in weaker vaccine responses.\n                  <\/jats:p>","DOI":"10.1111\/acel.70438","type":"journal-article","created":{"date-parts":[[2026,3,9]],"date-time":"2026-03-09T15:55:42Z","timestamp":1773071742000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Altered Cytokine\u2010Induced\n                    <scp>STAT3<\/scp>\n                    and\n                    <scp>STAT5<\/scp>\n                    Activation of Peripheral T Follicular Helper Cells Contributes to Vaccine\u2010Non\u2010Responsiveness in Aging and\n                    <scp>HIV<\/scp>"],"prefix":"10.1111","volume":"25","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-0199-0160","authenticated-orcid":false,"given":"Sheldon","family":"Davis","sequence":"first","affiliation":[{"name":"Department of Microbiology and Immunology University of Miami Miller School of Medicine  Florida USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jonah","family":"Kupritz","sequence":"additional","affiliation":[{"name":"Department of Microbiology and Immunology University of Miami Miller School of Medicine  Florida USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Prabhsimran","family":"Singh","sequence":"additional","affiliation":[{"name":"Department of Microbiology and Immunology University of Miami Miller School of Medicine  Florida USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Savita","family":"Pahwa","sequence":"additional","affiliation":[{"name":"Department of Microbiology and Immunology University of Miami Miller School of Medicine  Florida USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Suresh","family":"Pallikkuth","sequence":"additional","affiliation":[{"name":"Department of Microbiology and Immunology University of Miami Miller School of Medicine  Florida USA"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"311","published-online":{"date-parts":[[2026,3,9]]},"reference":[{"key":"e_1_2_10_2_1","doi-asserted-by":"publisher","DOI":"10.1172\/jci.insight.132155"},{"key":"e_1_2_10_3_1","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0286436"},{"key":"e_1_2_10_4_1","doi-asserted-by":"publisher","DOI":"10.1084\/jem.20091706"},{"key":"e_1_2_10_5_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.immuni.2024.08.019"},{"key":"e_1_2_10_6_1","unstructured":"Centers for Disease Control and Prevention.2022.\u201cAntigenic 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